Optimised ion mobility separation timescales for targeted ions

ABSTRACT

An analytical device for analysing ions is provided comprising a separator 2 for separating ions according to a physico-chemical property and an interface 3 comprising one or more ion guides. A quadrupole rod set mass filter 4 is arranged downstream of the interface 3. A control system is arranged and adapted: (i) to transmit a first group of ions which emerges from the separator 2 through the interface 3 with a first transit time t1; and (ii) to transmit a second group of ions which subsequently emerges from the separator 2 through the interface 3 with a second different transit time t2.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from and the benefit of United Kingdompatent application No. 1304037.3 filed on 6 Mar. 2013 and Europeanpatent application No. 13158047.4 filed 6 Mar. 2013. The entire contentsof these applications are incorporated herein by reference.

BACKGROUND TO THE PRESENT INVENTION

The present invention relates to an analytical device, a massspectrometer, a method of analysing ions and a method of massspectrometry. The preferred embodiment relates to an ion mobilityseparator (“IMS”) which is coupled to and arranged upstream of aquadrupole rod set mass filter.

The timescales associated with ion mobility separators or spectrometers(“IMS”) present practical difficulties such as the ability of aresolving quadrupole (“Q”) arranged downstream of an ion mobilityspectrometer to switch between transmitting different components in asingle ion mobility spectrometer or separator experiment or cycle.

A particular problem with conventional mass spectrometers comprising anion mobility spectrometer arranged upstream of a quadrupole mass filteris that the ion mobility separation timescales (e.g. 200 μs) of closelyeluting analyte ions from the ion mobility spectrometer can be too fastfor the quadrupole which may take e.g. 1 ms to switch mass to chargeratio transmission windows. As a result, the ion mobility spectrometerplaces significant limitations on system performance such as the dynamicrange of ion detectors in a mass spectrometer comprising an ion mobilityspectrometer, a quadrupole mass filter and a Time of Flight massanalyser.

US 2002/0070338 (Loboda) discloses in FIG. 5 an ion mobility section 66and a quadrupole rod set 78 arranged upstream of a time of flight massanalyser 90.

WO 02/07185 (Clemmer) discloses in FIG. 17 an arrangement wherein an ionmobility spectrometer 34 is arranged upstream of a time of flight massanalyser 36.

US 2005/0242279 (Verentchikov) discloses a tandem time of flight massspectrometer.

US 2011/0127417 (Ibrahim) discloses a system and method for collisionalactivation of charged particles.

GB 2497958 (Makarov) discloses a collision cell for tandem massspectrometry.

GB-2391697 (Micromass) discloses a mass spectrometer having an ion guidewhich receives ions and emits ions in a synchronised manner with anorthogonal acceleration Time of Flight mass analyser.

GB-2397433 (Micromass) discloses a mass spectrometer wherein ions from apulsed ion source are received by an ion guide in which multipletrapping regions are created.

GB-2451149 (Micromass) discloses a dual mode ion mobility mass analyserdevice.

GB-2421840 (Micromass) discloses a mass spectrometer comprising an ionguide located downstream of an ion mobility spectrometer.

GB-2485667 (Micromass) discloses a mass spectrometer comprising a gasphase ion-neutral reaction device arranged to perform Hydrogen-Deuteriumexchange.

It is desired to provide an improved mass spectrometer and method ofmass spectrometry.

SUMMARY OF THE PRESENT INVENTION

According to an aspect of the present invention there is provided ananalytical device for analysing ions comprising:

a separator for separating ions according to a physico-chemicalproperty;

an interface comprising one or more ion guides, each ion guidecomprising a plurality of electrodes;

a quadrupole rod set mass or mass to charge ratio filter arrangeddownstream of the interface; and

a control system arranged and adapted:

(i) to transmit a first group of ions which emerges from the separatorthrough the interface with a first transit time t1; and

(ii) to transmit a second group of ions which subsequently emerges fromthe separator through the interface with a second different transit timet2.

US 2002/0070338 (Loboda) does not disclose providing an interfacebetween an ion mobility spectrometer and a quadrupole mass filter andarranging to transmit groups of ions which emerge from the ion mobilityspectrometer through the interface with different transit times so as toallow a relatively fast ion mobility spectrometer to be coupled to arelatively slow quadrupole mass filter.

The preferred embodiment of the present invention alleviates some of thedrawbacks associated with the fast separation timescales of ion mobilitydevices and in particular enables a relatively fast separator such as anion mobility spectrometer or separator device (or other separators) tobe interfaced to a slower device such as a quadrupole mass filter.

Optimised ion mobility separation timescales for targeted ions is a newmode of operation implementable on existing and future ion mobilityspectrometer or separator based instruments.

The present invention enables the experimental timescales of ionsseparated by ion mobility and then filtered by mass to charge ratio tobe altered so as to improve the performance of the system as a whole.

The present invention may be extended to other embodiments wherein thequadrupole rod set mass filter may be replaced by another ion-opticaldevice or component. The ion-optical device or component preferably hasa slower response time than the separation time of two closely elutingions which are separated temporally by the upstream separator. It shouldbe understood, therefore, that the provision of a quadrupole rod setmass filter although desirable is not essential to the presentinvention.

According to an aspect of the present invention there is provided ananalytical device for analysing ions comprising:

a separator for separating ions according to a physico-chemicalproperty;

an interface; and

a control system arranged and adapted:

(i) to transmit a first group of ions which emerges from the separatorthrough the interface with a first transit time t1; and

(ii) to transmit a second group of ions which subsequently emerges fromthe separator through the interface with a second different transit timet2.

The physico-chemical property preferably comprises ion mobility ordifferential ion mobility.

The separator preferably comprises an ion mobility separator or adifferential ion mobility separator.

The physico-chemical property preferably comprises mass or mass tocharge ratio.

The separator preferably comprises a time of flight region.

The control system is preferably arranged and adapted to transmit thesecond group of ions through the interface with a transit time t2,wherein t2>t1.

The interface preferably comprises one or more ion guides, each ionguide comprising a plurality of electrodes.

The control system is preferably further arranged and adapted to applyone or more transient DC voltages or potentials to the plurality ofelectrodes so that the first group of ions are translated along the oneor more ion guides with a first velocity.

The control system is preferably further arranged and adapted to applyone or more transient DC voltages or potentials to the plurality ofelectrodes so that the second group of ions are translated along the oneor more ion guides with a second different velocity.

The second velocity is preferably slower than the first velocity.

The control system is preferably further arranged and adapted tomaintain at a first time a first DC voltage or potential gradient alongthe one or more ion guides so that the first group of ions are urgedalong the one or more ion guides with a first velocity.

The control system is preferably further arranged and adapted tomaintain at a second later time a second DC voltage or potentialgradient along the one or more ion guides so that the second group ofions are urged along the one or more ion guides with a second differentvelocity.

The second DC voltage or potential gradient is preferably less than thefirst DC voltage or potential gradient.

The analytical device preferably further comprises a filter arrangeddownstream of the interface. The filter preferably comprises a mass ormass to charge ratio filter. The filter preferably comprises aquadrupole rod set mass or mass to charge ratio filter.

The control system is preferably further arranged and adjusted:

(i) to cause the mass or mass to charge ratio filter to transmit ionshaving masses or mass to charge ratios within a first mass or mass tocharge ratio range; and then

(ii) to cause the mass or mass to charge ratio filter to transmit ionshaving masses or mass to charge ratios within a second different mass ormass to charge ratio range.

The filter preferably comprises an ion mobility or differential ionmobility filter. The control system is preferably further arranged andadjusted:

(i) to cause the ion mobility or differential ion mobility filter totransmit ions having an ion mobility or differential ion mobility withina first ion mobility or differential ion mobility range; and then

(ii) to cause the ion mobility or differential ion mobility filter totransmit ions having an ion mobility or differential ion mobility withina second different ion mobility or differential ion mobility range.

The control system is preferably arranged and adapted to transmit thefirst group of ions which emerges from the separator through theinterface with a first transit time t1 and to transmit the second groupof ions which subsequently emerges from the separator through theinterface with a second different transit time t2 within or during asingle cycle of separation of ions within the separator.

According to an aspect of the present invention there is provided a massspectrometer comprising an analytical device as described above.

According to an aspect of the present invention there is provided amethod of analysing ions comprising:

separating ions according to a physico-chemical property in a separator;

providing an interface comprising one or more ion guides, each ion guidecomprising a plurality of electrodes and a quadrupole rod set mass ormass to charge ratio filter arranged downstream of said interface;

transmitting a first group of ions which emerges from the separatorthrough the interface with a first transit time t1; and

transmitting a second group of ions which subsequently emerges from theseparator through the interface with a second different transit time t2.

The steps of transmitting the first group of ions which emerges from theseparator through the interface with a first transit time t1 andtransmitting the second group of ions which subsequently emerges fromthe separator through the interface with a second different transit timet2 are preferably performed within or during a single cycle ofseparation of ions within the separator.

According to an aspect of the present invention there is provided methodof mass spectrometry comprising a method as described above.

According to an aspect of the present invention there is provided ananalytical device for analysing ions comprising:

a separator for separating ions according to a physico-chemicalproperty;

an interface; and

a control system arranged and adapted:

(i) to transmit a first group of ions which emerges from the separatorthrough a first ion path through the interface with a first transit timet1; and

(ii) to transmit a second group of ions which subsequently emerges fromthe separator through a second different (e.g. longer) ion path throughthe interface with a second different transit time t2.

The control system is preferably arranged and adapted to transmit thefirst group of ions which emerges from the separator through a first ionpath through the interface with a first transit time t1 and to transmita second group of ions which subsequently emerges from the separatorthrough a second different (e.g. longer) ion path through the interfacewith a second different transit time t2 within or during a single cycleof separation of ions within the separator.

According to an aspect of the present invention there is provided amethod of analysing ions comprising:

separating ions according to a physico-chemical property in a separator;

providing an interface;

transmitting a first group of ions which emerges from the separatorthrough a first ion path through the interface with a first transit timet1; and

transmitting a second group of ions which subsequently emerges from theseparator through a second different (e.g. longer) ion path through theinterface with a second different transit time t2.

The steps of transmitting the first group of ions which emerges from theseparator through a first ion path through the interface with a firsttransit time t1 and transmitting a second group of ions whichsubsequently emerges from the separator through a second different (e.g.longer) ion path through the interface with a second different transittime t2 are preferably performed within or during a single cycle ofseparation of ions within the separator.

According to an aspect of the present invention there is provided ananalytical device for analysing ions comprising:

a separator for separating ions according to a physico-chemicalproperty;

an interface; and

a control system arranged and adapted within a single cycle ofseparation of ions within the separator to transmit a first group ofions which emerges from the separator through the interface with a firsttransit time t1 and to transmit a second group of ions whichsubsequently emerges from the separator through the interface with asecond different transit time t2.

According to an aspect of the present invention there is provided amethod of analysing ions comprising:

separating ions according to a physico-chemical property in a separator;

providing an interface; and

during a single cycle of separation of ions within the separatortransmitting a first group of ions which emerges from the separatorthrough the interface with a first transit time t1 and transmitting asecond group of ions which subsequently emerges from the separatorthrough the interface with a second different transit time t2.

According to an embodiment the mass spectrometer may further comprise:

(a) an ion source selected from the group consisting of: (i) anElectrospray ionisation (“ESI”) ion source; (ii) an Atmospheric PressurePhoto Ionisation (“APPI”) ion source; (iii) an Atmospheric PressureChemical Ionisation (“APCI”) ion source; (iv) a Matrix Assisted LaserDesorption Ionisation (“MALDI”) ion source; (v) a Laser DesorptionIonisation (“LDI”) ion source; (vi) an Atmospheric Pressure Ionisation(“API”) ion source; (vii) a Desorption Ionisation on Silicon (“DIOS”)ion source; (viii) an Electron Impact (“EI”) ion source; (ix) a ChemicalIonisation (“CI”) ion source; (x) a Field Ionisation (“FI”) ion source;(xi) a Field Desorption (“FD”) ion source; (xii) an Inductively CoupledPlasma (“ICP”) ion source; (xiii) a Fast Atom Bombardment (“FAB”) ionsource; (xiv) a Liquid Secondary Ion Mass Spectrometry (“LSIMS”) ionsource; (xv) a Desorption Electrospray Ionisation (“DESI”) ion source;(xvi) a Nickel-63 radioactive ion source; (xvii) an Atmospheric PressureMatrix Assisted Laser Desorption Ionisation ion source; (xviii) aThermospray ion source; (xix) an Atmospheric Sampling Glow DischargeIonisation (“ASGDI”) ion source; (xx) a Glow Discharge (“GD”) ionsource; (xxi) an Impactor ion source; (xxii) a Direct Analysis in RealTime (“DART”) ion source; (xxiii) a Laserspray Ionisation (“LSI”) ionsource; (xxiv) a Sonicspray Ionisation (“SSI”) ion source; (xxv) aMatrix Assisted Inlet Ionisation (“MAII”) ion source; and (xxvi) aSolvent Assisted Inlet Ionisation (“SAII”) ion source; and/or

(b) one or more continuous or pulsed ion sources; and/or

(c) one or more ion guides; and/or

(d) one or more ion mobility separation devices and/or one or more FieldAsymmetric Ion Mobility Spectrometer devices; and/or

(e) one or more ion traps or one or more ion trapping regions; and/or

(f) one or more collision, fragmentation or reaction cells selected fromthe group consisting of: (i) a Collisional Induced Dissociation (“CID”)fragmentation device; (ii) a Surface Induced Dissociation (“SID”)fragmentation device; (iii) an Electron Transfer Dissociation (“ETD”)fragmentation device; (iv) an Electron Capture Dissociation (“ECD”)fragmentation device; (v) an Electron Collision or Impact Dissociationfragmentation device; (vi) a Photo Induced Dissociation (“PID”)fragmentation device; (vii) a Laser Induced Dissociation fragmentationdevice; (viii) an infrared radiation induced dissociation device; (ix)an ultraviolet radiation induced dissociation device; (x) anozzle-skimmer interface fragmentation device; (xi) an in-sourcefragmentation device; (xii) an in-source Collision Induced Dissociationfragmentation device; (xiii) a thermal or temperature sourcefragmentation device; (xiv) an electric field induced fragmentationdevice; (xv) a magnetic field induced fragmentation device; (xvi) anenzyme digestion or enzyme degradation fragmentation device; (xvii) anion-ion reaction fragmentation device; (xviii) an ion-molecule reactionfragmentation device; (xix) an ion-atom reaction fragmentation device;(xx) an ion-metastable ion reaction fragmentation device; (xxi) anion-metastable molecule reaction fragmentation device; (xxii) anion-metastable atom reaction fragmentation device; (xxiii) an ion-ionreaction device for reacting ions to form adduct or product ions; (xxiv)an ion-molecule reaction device for reacting ions to form adduct orproduct ions; (xxv) an ion-atom reaction device for reacting ions toform adduct or product ions; (xxvi) an ion-metastable ion reactiondevice for reacting ions to form adduct or product ions; (xxvii) anion-metastable molecule reaction device for reacting ions to form adductor product ions; (xxviii) an ion-metastable atom reaction device forreacting ions to form adduct or product ions; and (xxix) an ElectronIonisation Dissociation (“EID”) fragmentation device; and/or

(g) a mass analyser selected from the group consisting of: (i) aquadrupole mass analyser; (ii) a 2D or linear quadrupole mass analyser;(iii) a Paul or 3D quadrupole mass analyser; (iv) a Penning trap massanalyser; (v) an ion trap mass analyser; (vi) a magnetic sector massanalyser; (vii) Ion Cyclotron Resonance (“ICR”) mass analyser; (viii) aFourier Transform Ion Cyclotron Resonance (“FTICR”) mass analyser; (ix)an electrostatic mass analyser arranged to generate an electrostaticfield having a quadro-logarithmic potential distribution; (x) a FourierTransform electrostatic mass analyser; (xi) a Fourier Transform massanalyser; (xii) a Time of Flight mass analyser; (xiii) an orthogonalacceleration Time of Flight mass analyser; and (xiv) a linearacceleration Time of Flight mass analyser; and/or

(h) one or more energy analysers or electrostatic energy analysers;and/or

(i) one or more ion detectors; and/or

(j) one or more mass filters selected from the group consisting of: (i)a quadrupole mass filter; (ii) a 2D or linear quadrupole ion trap; (iii)a Paul or 3D quadrupole ion trap; (iv) a Penning ion trap; (v) an iontrap; (vi) a magnetic sector mass filter; (vii) a Time of Flight massfilter; and (viii) a Wien filter; and/or

(k) a device or ion gate for pulsing ions; and/or

(l) a device for converting a substantially continuous ion beam into apulsed ion beam.

The mass spectrometer may further comprise either:

(i) a C-trap and a mass analyser comprising an outer barrel-likeelectrode and a coaxial inner spindle-like electrode that form anelectrostatic field with a quadro-logarithmic potential distribution,wherein in a first mode of operation ions are transmitted to the C-trapand are then injected into the mass analyser and wherein in a secondmode of operation ions are transmitted to the C-trap and then to acollision cell or Electron Transfer Dissociation device wherein at leastsome ions are fragmented into fragment ions, and wherein the fragmentions are then transmitted to the C-trap before being injected into themass analyser; and/or

(ii) a stacked ring ion guide comprising a plurality of electrodes eachhaving an aperture through which ions are transmitted in use and whereinthe spacing of the electrodes increases along the length of the ionpath, and wherein the apertures in the electrodes in an upstream sectionof the ion guide have a first diameter and wherein the apertures in theelectrodes in a downstream section of the ion guide have a seconddiameter which is smaller than the first diameter, and wherein oppositephases of an AC or RF voltage are applied, in use, to successiveelectrodes.

According to an embodiment the mass spectrometer further comprises adevice arranged and adapted to supply an AC or RF voltage to theelectrodes. The AC or RF voltage preferably has an amplitude selectedfrom the group consisting of: (i) <50 V peak to peak; (ii) 50-100 V peakto peak; (iii) 100-150 V peak to peak; (iv) 150-200 V peak to peak; (v)200-250 V peak to peak; (vi) 250-300 V peak to peak; (vii) 300-350 Vpeak to peak; (viii) 350-400 V peak to peak; (ix) 400-450 V peak topeak; (x) 450-500 V peak to peak; and (xi) >500 V peak to peak.

The AC or RF voltage preferably has a frequency selected from the groupconsisting of: (i) <100 kHz; (ii) 100-200 kHz; (iii) 200-300 kHz; (iv)300-400 kHz; (v) 400-500 kHz; (vi) 0.5-1.0 MHz; (vii) 1.0-1.5 MHz;(viii) 1.5-2.0 MHz; (ix) 2.0-2.5 MHz; (x) 2.5-3.0 MHz; (xi) 3.0-3.5 MHz;(xii) 3.5-4.0 MHz; (xiii) 4.0-4.5 MHz; (xiv) 4.5-5.0 MHz; (xv) 5.0-5.5MHz; (xvi) 5.5-6.0 MHz; (xvii) 6.0-6.5 MHz; (xviii) 6.5-7.0 MHz; (xix)7.0-7.5 MHz; (xx) 7.5-8.0 MHz; (xxi) 8.0-8.5 MHz; (xxii) 8.5-9.0 MHz;(xxiii) 9.0-9.5 MHz; (xxiv) 9.5-10.0 MHz; and (xxv) >10.0 MHz.

The mass spectrometer may also comprise a chromatography or otherseparation device upstream of an ion source. According to an embodimentthe chromatography separation device comprises a liquid chromatographyor gas chromatography device. According to another embodiment theseparation device may comprise: (i) a Capillary Electrophoresis (“CE”)separation device; (ii) a Capillary Electrochromatography (“CEC”)separation device; (iii) a substantially rigid ceramic-based multilayermicrofluidic substrate (“ceramic tile”) separation device; or (iv) asupercritical fluid chromatography separation device.

The ion guide is preferably maintained at a pressure selected from thegroup consisting of: (i) <0.0001 mbar; (ii) 0.0001-0.001 mbar; (iii)0.001-0.01 mbar; (iv) 0.01-0.1 mbar; (v) 0.1-1 mbar; (vi) 1-10 mbar;(vii) 10-100 mbar; (viii) 100-1000 mbar; and (ix) >1000 mbar.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the present invention will now be described, byway of example only, and with reference to the accompanying drawings inwhich:

FIG. 1 shows a mass spectrometer according to an embodiment of thepresent invention comprising an ion mobility spectrometer or separatordevice, an interface or transfer device, a quadrupole rod set massfilter, a gas cell and an orthogonal acceleration Time of Flight massanalyser;

FIG. 2 shows the temporal separation of two ions of interest withrespect to the start of an ion mobility experiment at positions A, B andD as shown in FIG. 1;

FIG. 3 shows how the difference in timescale between the separation ofions using an ion mobility spectrometer or separator device and theability to switch a quadrupole mass filter can limit the effectivenessof the isolation stage;

FIG. 4 illustrates the effect of increasing the transit time of ionsthrough an interface or transfer region in accordance with a preferredembodiment of the present invention;

FIG. 5 shows two components separated at the exit of the gas cell;

FIG. 6 shows how according to an embodiment the gas cell may beconfigured to allow some loss of fidelity of the IMS peaks in order toimprove dynamic range; and

FIG. 7 shows a further embodiment wherein an ion gate is providedupstream of the interface or transfer device.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT

FIG. 1 shows a simplified schematic of a IMS-Q-ToF mass spectrometeraccording to an embodiment of the present invention. The massspectrometer comprises an ion mobility separator (“IMS”) 2, an interfaceor transfer device 3, a quadrupole rod set mass filter 4, a gas orreaction cell 5 and an orthogonal acceleration Time of Flight massanalyser 6. Various different types of experiments may be performedutilising this instrument geometry. In particular, the quadrupole massfilter 4 which is preferably arranged downstream of the ion mobilityspectrometer or separator device 2 may be utilised to select specificparent or precursor ions.

According to an embodiment ions may be separated according to their ionmobility in the ion mobility spectrometer or separator device 2. Theions are then preferably transported through the interface, transferdevice or transfer region 3 to the quadrupole mass filter 4 which ispreferably arranged to operate in a resolving mode. The quadrupole massfilter 4 preferably switches between components of interest which elutefrom the ion mobility spectrometer or separator device 2 within a singleion mobility spectrometer or separator cycle or single cycle ofseparation thereby providing both improved selectivity (due to thepartially orthogonal nature of ion mobility and mass to charge ratioseparations) and also improved duty cycle (due to the temporalpre-separation of the ions before quadrupole filtering). This approachprovides significant improvements over standard MSMS approaches for bothtargeted experiments where the mass to charge ratio and ion mobility ofcomponents of interest are derived from a library/method developmentstage and also for Data Dependent Acquisitions (“DDA”) where the mass tocharge ratio and ion mobility are derived from an initial survey scan.

FIG. 2 shows the temporal separation of two ions of interest withrespect to the start of an ion mobility experiment at positions A, B andD within a mass spectrometer as shown in FIG. 1 during a single cycle ofseparation.

In FIG. 2 the time taken by ions to reach position A is dominated by themobility of the ions. The ion mobility provides a mechanism ofseparation as shown by the temporal separation of the two components.The two components of interest also have different mass to charge ratiovalues as shown in FIG. 2 although, at position A, no mass to chargeratio based separation has yet occurred.

On exiting the ion mobility spectrometer or separator region 2 the ionspreferably enter an interface or transfer region 3 which according to anembodiment may comprise a travelling wave ion guide (“TWIG”). Theinterface or transfer region 3 is preferably maintained at anintermediate pressure between that of the ion mobility spectrometer orseparator device 2 and the quadrupole mass filter 4. The travelling waveion guide preferably transports ions at a fixed velocity such that thetimes at position B are further increased by a value TB-TA which isrelated to the length of the travelling wave ion guide and the speed ofthe travelling wave. For example, a 50 mm long travelling wave ion guideoperated with a travelling wave speed of 300 m/s would introduce atemporal shift of approximately 167 μs. Again, at this position withinthe instrument no mass to charge separation has yet occurred.

A similar time shift is observed for ions transiting the gas cell 5 toreach position D although the ions at this point may comprise fragmentions related to components 1 and 2 and at a similar time to components 1and 2. For illustrative purposes only the two components shown in FIG. 2have not undergone fragmentation. As the ions transit between position Band position C they preferably pass through a resolving quadrupole massfilter 4 that preferably sequentially isolates the mass to charge ratiosof components 1 and 2 at the appropriate times thereby improvingselectivity and duty cycle.

The above described approach affords significant advantages overconventional systems. However, it does nonetheless suffer from somelimitations. The present invention seeks to address some of theselimitations.

One drawback with the approach described above with reference to FIG. 1is that the ion mobility spectrometer or separator separation timesbetween two closely eluting components may be significantly shorter thanthe speed at which the resolving quadrupole mass filter 4 can switchbetween two mass to charge ratio settings.

The time taken to switch a quadrupole mass filter 4 between differentmass to charge ratio settings depends on a number of parametersincluding the settling time of various electronic components and thetime of flight through the resolving quadrupole mass filter 4. Typicalvalues for this switching time are of the order of 1 ms. By contrast,two baseline resolved components with nominal transit times through alinear drift tube ion mobility spectrometer or separator device of 5 msand which operates at a resolution of 50 might be separated in time byonly 200 μs. It will be apparent, therefore, that the quadrupole 4 maybe unable to switch mass to charge ratio transmission windows on thistimescale.

FIG. 3 illustrates in more detail how the difference in timescalebetween the ion mobility spectrometer or separator device 2 and theswitching of the quadrupole mass filter 4 can limit the effectiveness ofthe isolation stage. FIG. 3 shows a system operating at an approximateion mobility spectrometer or separator resolution of 50 (FWHM) and showstwo components arriving at position B (i.e. at the exit of the ionmobility spectrometer or separator device 2) with nominal transit timesof 5 ms. However, the two components are actually separated by 0.4 msand are therefore fully baseline resolved. The quadrupole mass filter 4is switched at a time T_(s) immediately after the last of component 1has eluted from the ion mobility spectrometer or separator device 2.However, the time taken for the quadrupole mass filter 4 to switch massto charge ratio transmission windows in order to select between thesetwo components is T_(q) and it is apparent from FIG. 3 that component 2will arrive at the quadrupole mass filter 4 before time T_(s)+T_(q). Asa result, component 2 will arrive at the mass filter 4 before the massfilter 4 has had sufficient time to switch to transmit ions having massto charge ratios corresponding with component 2. As a result, component2 will not be onwardly transmitted by the mass filter 4. Thiseffectively limits the resolution of the filtering or isolation stage.

According to an embodiment of the present invention an improvement tothis approach is to delay component 2 by introducing an interface ortransfer device 3 between the ion mobility spectrometer or separatordevice 2 and the quadrupole mass filter 4 and by altering the transittime across or through the interface or transfer region 3 during asingle cycle of separation. This may be achieved by, for example,altering (i.e. reducing) the speed of a travelling wave applied to theinterface or transfer ion guide 3 after component 1 has exited oremerged from the interface or transfer device 3 during a single cycle ofseparation.

FIG. 4 shows the effect of reducing the speed of the travelling waveapplied to electrodes of the interface from 300 m/s to 60 m/s aftercomponent 1 has exited the interface or transfer travelling wave ionguide 3. For a transfer travelling wave ion guide 3 having a length of50 mm the transit time for component 2 to traverse the interface ortransfer travelling wave ion guide 3 is increased by 833 μs. This shiftor increase in transit time ensures that component 2 will now arrive atthe quadrupole mass filter 4 after the quadrupole mass filter 4 hasswitched and has had sufficient time to settle thereby ensuring onwardtransmission of component 2. In this case the resolution of theisolation stage is now related to the transit time through the interfaceor transfer device 3.

It is worth noting that the separation in time for a given ion mobilityspectrometer or separator resolution can be significantly different forion mobility spectrometer or separator instruments not using lineardrift tubes such as T-Wave based ion mobility spectrometer or separatordevices depending on the power term (X) in the relationship T=A×K^(X)where T is the drift time, K is the mobility and A is a constant. Thisdifference can either aid or hinder the effects of previously describedquadrupole switching limitation.

A second drawback of the approach described above with reference to FIG.3 is that the ion mobility separation also introduces significantrestrictions to the dynamic range of the ion detecter system of anIMS-Q-ToF mass spectrometer due to the compression in time of any givencomponent and the limited intensity scale of the ion detection systemdigitisation.

FIG. 5 shows two components which are well separated and isolated inIMS-mass to charge ratio space at position D in FIG. 1 i.e. at the exitof the gas cell 5.

According to a further embodiment the gas cell 5 may be configured toallow some loss of fidelity of the ion mobility spectrometer orseparator peaks as shown in FIG. 6. As a result, a greater number oforthogonal acceleration Time of Flight pushes are now used to analysethe components. This advantageously increases the dynamic range of thesystem. The choice of the degree of loss of fidelity can be based ondegree of separation of the two components.

In both of the above examples the choice of two components is fordescriptive purposes only. In practice, more than two components may bechosen depending on separations or resolution etc.

Ions which are onwardly transmitted may be subjected to analyticaltechniques such as fragmentation, mass measurement or ion mobilitymeasurement etc.

Further embodiments are contemplated wherein the described approach isapplied with other fast pre quadrupole separators such as ion traps andmass to charge ratio separators.

According to another less preferred embodiment instead of switching thetransit delay in time, ions may alternatively be switched in space intodifferent transfer devices each having different effective transittimes.

According to another embodiment transfer devices 3 utilising approachesother than travelling waves such as axial fields may be used.

Other instrument improvements can be accessed via the approach accordingto the preferred embodiment. For example, components can be pushedtogether in time if they are over separated allowing shorter ionmobility spectrometer or separator cycle times thereby ultimatelyreducing space charge effects in pre ion mobility spectrometer orseparator accumulators.

The delay shifts may be introduced by devices operating at the samepressure as the ion mobility spectrometer or separator device 2.

The delay shifts can also be introduced by altering the parameters ofthe ion mobility spectrometer or separator device 2 itself.

A continuous stretching of the time axis may be realised by continuallyand monotonically slowing the travelling wave speed so as to improve theability of a scanning quadrupole mass filter 4 to track ions elutingfrom the ion mobility spectrometer or separator device 2 or to improvethe digitisation of the ion mobility spectrometer or separator device 2by, for example, the orthogonal acceleration Time of Flight massanalyser 6.

Transfer devices 3 with transit speeds that vary as a function of lengthmay be utilised as well as transfer devices with accumulation regions.

The quadrupole mass filter 4 preferably provides isolation in both timeand mass to charge ratio. However, in practice different devices may beused to provide time isolation (e.g. an ion gate 7) and mass to chargeratio isolation (e.g. a quadrupole mass filter 4). FIG. 7 shows aschematic of an example of this type of geometry.

In the embodiment shown in FIG. 7 time regions corresponding to theregions containing components of interest are selected by the ion gate7. The ion gate 7 may be part of the ion mobility spectrometer orseparator device 2 or the transfer device 3 and is shown in FIG. 7 as aseparate component for illustrative purpose only. The time selectedregions may then be partitioned by the transfer travelling wave ionguide 3 and their temporal separations adjusted as they transit thetransfer travelling wave ion guide 3 so as to allow efficient deliveryto the resolving quadrupole mass filter 4. The previously describedposition dependent travelling wave speed travelling wave ion guide withaccumulation regions is particularly beneficial for this approach.

Although the present invention has been described with reference topreferred embodiments, it will be understood by those skilled in the artthat various changes in form and detail may be made without departingfrom the scope of the invention as set forth in the accompanying claims.

1. An analytical device for analysing ions comprising: a separator forseparating ions according to a physico-chemical property; an interfacecomprising one or more ion guides, each ion guide comprising a pluralityof electrodes; a quadrupole rod set mass or mass to charge ratio filterarranged downstream of said interface; and a control system arranged andadapted: (i) to transmit a first group of ions which emerges from saidseparator through said interface with a first transit time t1; and (ii)to transmit a second group of ions which subsequently emerges from saidseparator through said interface with a second different transit timet2.
 2. An analytical device as claimed in claim 1, wherein saidphysico-chemical property comprises ion mobility or differential ionmobility.
 3. An analytical device as claimed in claim 2, wherein saidseparator comprises an ion mobility separator or a differential ionmobility separator.
 4. An analytical device as claimed in claim 1,wherein said physico-chemical property comprises mass or mass to chargeratio.
 5. An analytical device as claimed in claim 4, wherein saidseparator comprises a time of flight region.
 6. An analytical device asclaimed in any preceding claim, wherein said control system is arrangedand adapted to transmit said second group of ions through said interfacewith a transit time t2, wherein t2>t1.
 7. An analytical device asclaimed in any preceding claim, wherein said control system is furtherarranged and adapted to apply one or more transient DC voltages orpotentials to said plurality of electrodes so that said first group ofions are translated along said one or more ion guides with a firstvelocity.
 8. An analytical device as claimed in claim 7, wherein saidcontrol system is further arranged and adapted to apply one or moretransient DC voltages or potentials to said plurality of electrodes sothat said second group of ions are translated along said one or more ionguides with a second different velocity.
 9. An analytical device asclaimed in claim 8, wherein said second velocity is slower than saidfirst velocity.
 10. An analytical device as claimed in any precedingclaim, wherein said control system is further arranged and adapted tomaintain at a first time a first DC voltage or potential gradient alongsaid one or more ion guides so that said first group of ions are urgedalong said one or more ion guides with a first velocity.
 11. Ananalytical device as claimed in claim 10, wherein said control system isfurther arranged and adapted to maintain at a second later time a secondDC voltage or potential gradient along said one or more ion guides sothat said second group of ions are urged along said one or more ionguides with a second different velocity.
 12. An analytical device asclaimed in claim 11, wherein said second DC voltage or potentialgradient is less than said first DC voltage or potential gradient. 13.An analytical device as claimed in any preceding claim, wherein saidcontrol system is further arranged and adjusted: (i) to cause said massor mass to charge ratio filter to transmit ions having masses or mass tocharge ratios within a first mass or mass to charge ratio range; andthen (ii) to cause said mass or mass to charge ratio filter to transmitions having masses or mass to charge ratios within a second differentmass or mass to charge ratio range.
 14. An analytical device as claimedin any preceding claim, wherein said control system is arranged andadapted to transmit said first group of ions which emerges from saidseparator through said interface with a first transit time t1 and totransmit said second group of ions which subsequently emerges from saidseparator through said interface with a second different transit time t2within or during a single cycle of separation of ions within saidseparator.
 15. A mass spectrometer comprising an analytical device asclaimed in any preceding claim.
 16. A method of analysing ionscomprising: separating ions according to a physico-chemical property ina separator; providing an interface comprising one or more ion guides,each ion guide comprising a plurality of electrodes and a quadrupole rodset mass or mass to charge ratio filter arranged downstream of saidinterface; transmitting a first group of ions which emerges from saidseparator through said interface with a first transit time t1; andtransmitting a second group of ions which subsequently emerges from saidseparator through said interface with a second different transit timet2.
 17. A method as claimed in claim 16, wherein the steps oftransmitting said first group of ions which emerges from said separatorthrough said interface with a first transit time t1 and transmittingsaid second group of ions which subsequently emerges from said separatorthrough said interface with a second different transit time t2 areperformed within or during a single cycle of separation of ions withinsaid separator.
 18. A method of mass spectrometry comprising a method asclaimed in claim 16 or
 17. 19. An analytical device for analysing ionscomprising: a separator for separating ions according to aphysico-chemical property; an interface; a quadrupole rod set mass ormass to charge ratio filter arranged downstream of said interface; and acontrol system arranged and adapted: (i) to transmit a first group ofions which emerges from said separator through a first ion path throughsaid interface with a first transit time t1; and (ii) to transmit asecond group of ions which subsequently emerges from said separatorthrough a second different ion path through said interface with a seconddifferent transit time t2.
 20. An analytical device as claimed in claim19, wherein said control system is arranged and adapted to transmit saidfirst group of ions which emerges from said separator through a firstion path through said interface with a first transit time t1 and totransmit a second group of ions which subsequently emerges from saidseparator through a second different ion path through said interfacewith a second different transit time t2 within or during a single cycleof separation of ions within said separator.
 21. A method of analysingions comprising: separating ions according to a physico-chemicalproperty in a separator; providing an interface and a quadrupole rod setmass or mass to charge ratio filter arranged downstream of saidinterface; transmitting a first group of ions which emerges from saidseparator through a first ion path through said interface with a firsttransit time t1; and transmitting a second group of ions whichsubsequently emerges from said separator through a second different ionpath through said interface with a second different transit time t2. 22.A method as claimed in claim 21, wherein the steps of transmitting saidfirst group of ions which emerges from said separator through a firstion path through said interface with a first transit time t1 andtransmitting a second group of ions which subsequently emerges from saidseparator through a second different ion path through said interfacewith a second different transit time t2 are performed within or during asingle cycle of separation of ions within said separator.